There is a fundamental gap in knowledge regarding host susceptibility and mechanisms of drug-induced liver injury (DILI) in humans. To date, the Drug Induced Liver Injury Network (DILIN) has succeeded in maintaining a prospective registry of well-defined cases with DILI to further research in this area. The long- term-goal is to understand the genetic influence on mechanisms and clinical outcomes of DILI. Critical to the success for improved understanding of pathogenesis, the objective of this application is to further expand the registry by including additional patients with DILI from geographic areas not currently within the Network. In response to RFA-DK-07-712 (Continuation and Expansion of the Drug Induced Liver Injury Network), the Central Hypothesis of this application is to effectively contribute well-definedcases of DILI and propose novel mechanistic studies examining phenotype-genotype associations. The proposed research is relevant to that part of the NIH mission which pertains to developing fundamental knowledge to reduce the burden of disease. This hypothesis will be tested by pursuing two specific aims. Specific Aim 1will focus on the identification and enrollment of cases with bona fide DILI and matched controls within a diverse racial and ethnic geographic population of 7 million individuals. Based on recent clinical experience with DILI, this consortium anticipates the enrollment of 250 cases affected by DILI and 750 matched controls with appropriate biospecimen collections over a 5 year period. Specific Aim 2 outlines a series of proposed experiments to determine whether differentialactivation of the unfolded protein response (UPR) from endoplasmic reticulum stress occurs in the pathogenesis of idiosyncratic DILI. The proposed work is innovative based on the coupling of advanced bioinformatics technology, extensive clinical experience, and recognized expertise in liver cell injury and genetic epidemiology. In turn, we are enthusiastic to work cooperatively with the Clinical Centers, the Data Coordinating Center, and sponsoring organizations in this expanded Network to oversee the implementation of and adherence to common protocols. RELEVANCE (See instructions): The proposed studies are of an important and under-investigated topic that has potential applicability for understanding the pathogenesis of more common liver diseases including hepatitis C and nonalcoholic steatohepatitis. The proposed research has relevance to public health, because the fundamental mechanisms to be investigated appear common for maintaining health and disease in human beings.